293 research outputs found
Wild monodromy and automorphisms of curves
Let be a complete discrete valuation ring of mixed characteristic
with field of fractions containing the -th roots of unity. This paper is
concerned with semi-stable models of -cyclic covers of the projective line
C \la \PK. We start by providing a new construction of a semi-stable model of
in the case of an equidistant branch locus. If the cover is given by the
Kummer equation we define what we called the monodromy polynomial
of ; a polynomial with coefficients in . Its zeros
are key to obtaining a semi-stable model of . As a corollary we obtain an
upper bound for the minimal extension over which a stable model of the
curve exists. Consider the polynomial where
the range over the zeros of . We show that the splitting
field of this polynomial always contains , and that in some instances the
two fields are equal.Comment: The final version of this article will be published in the Duke
Mathematical Journal, published by Duke University pres
Editorial: Innovative In Vitro Models for Pulmonary Physiology and Drug Delivery in Health and Disease
Towards a Continuous Manufacturing Process of Protein-Loaded Polymeric Nanoparticle Powders
To develop a scalable and efficient process suitable for the continuous manufacturing of poly(lactic-co-glycolic acid) (PLGA) nanoparticles containing ovalbumin as the model protein. PLGA nanoparticles were prepared using a double emulsification spray-drying method. Emulsions were prepared using a focused ultrasound transducer equipped with a flow cell. Either poly(vinyl alcohol) (PVA) or poloxamer 407 (P-407) was used as a stabilizer. Aliquots of the emulsions were blended with different matrix excipients and spray dried, and the yield and size of the resuspended nanoparticles was determined and compared against solvent displacement. Nanoparticle sizes of spray-dried PLGA/PVA emulsions were independent of the matrix excipient and comparable with sizes from the solvent displacement method. The yield of the resuspended nanoparticles was highest for emulsions containing trehalose and leucine (79%). Spray drying of PLGA/P-407 emulsions led to agglomerated nanoparticles independent of the matrix excipient. PLGA/P-407 nanoparticles pre-formed by solvent displacement could be spray dried with limited agglomeration when PVA was added as an additional stabilizer. A comparably high and economically interesting nanoparticle yield could be achieved with a process suitable for continuous manufacturing. Further studies are needed to understand the robustness of a continuous process at commercial scale
Human Skin Permeation Enhancement Using PLGA Nanoparticles Is Mediated by Local pH Changes
The steady improvement and optimization of transdermal permeation is a constant and
challenging pharmaceutical task. In this study the influence of poly(lactide-co-glycolide) (PLGA)
nanoparticles on the dermal permeation of the anti-inflammatory drug flufenamic acid (FFA) was
investigated. For this aim, different vehicles under non-buffered and buffered conditions and different
skin models (human heat separated epidermis and reconstructed human epidermis equivalents)
were tested. Permeation experiments were performed using static Franz diffusion cells under infinite
dosing conditions. Already the presence of drug-free nanoparticles increased drug permeation
across the skin. Drug permeation was even enhanced when applying drug-loaded nanoparticles. In
contrast, buffered vehicles with different pH values (pH 5.4â7.4) revealed the influence of the pH
on the permeation of FFA. The change of the surrounding pH of the biodegradable nanoparticulate
system was demonstrated and visualized using pH-sensitive fluorescent probes. While a potential
contribution of hair follicles could be ruled out, our data suggest that the enhanced permeation of
FFA through human skin in the presence of PLGA nanoparticles is mediated by a locally decreased
pH during hydrolytic degradation of this polymer. This hypothesis is supported by the observation
that skin permeation of the weak base caffeine was not affected
Itaconic Acid Increases the Efficacy of Tobramycin against Pseudomonas aeruginosa Biofilms
The search for novel therapeutics against pulmonary infections, in particular Pseudomonas aeruginosa (PA) biofilm infections, has been intense to deal with the emergent rise of antimicrobial resistance. Despite the numerous achievements in drug discovery and delivery strategies, only a limited number of therapeutics reach the clinic. To allow a timely preclinical development, a formulation should be highly effective, safe, and most importantly facile to produce. Thus, a simple combination of known actives that enhances the therapeutic efficacy would be a preferential choice compared to advanced drug delivery systems. In this study, we propose a novel combination of an anti-inflammatory agentâitaconic acid (itaconate, IA)âand an approved antibioticâtobramycin (Tob) or ciprofloxacin (Cipro). The combination of Tob and IA at a molar ratio of 1:5 increased the biofilm eradicating efficacy in the strain PA14 wild type (wt) by ~4-fold compared to Tob alone. In contrast, such effect was not observed for the combination of IA with Cipro. Subsequent studies on the influence of IA on bacterial growth, pyocyanin production, and Tob biofilm penetration indicated that complexation with IA enhanced the transport of Tob through the biofilm. We recommend the simple and effective combination of Tob:IA for further testing in advanced preclinical models of PA biofilm infections
Multiphoton microscopy for the investigation of dermal penetration of nanoparticle-borne drugs
Multiphoton microscopy of a dually fluorescence-labeled model system in excised human skin is employed for high resolution three dimensional visualization in order to study the release, accumulation and penetration properties of drugs released from nanoscale carrier particles in dermal administration. Polymer particles were covalently labeled with fluorescein while Texas Red as a drug-model was dissolved in the particle to be released to the formulation matrix. Single nanoparticles on skin could easily be localized and imaged with diffraction limited resolution. The temporal evolution of the fluorescent drug-model concentration in various skin compartments over more than five hours was investigated by multiphoton spectral imaging of the same area of the specimen. The three dimensional penetration profile of the drug-model in correlation with skin morphology and particle localization information are obtained by a multiple laser line excitation experiment. Multiphoton microscopy combined with spectral imaging was found to allow non invasive long term studies of particle-borne drug-model penetration into the skin with sub cellular resolution. By dual color labeling a clear discrimination between particle-bound and released drug-model was possible. The introduced technique was shown to be a powerful tool in revealing the dermal penetration properties and pathways of drugs and nanoscale drug vehicles on microscopic level
Co-Delivery of mRNA and pDNA Using Thermally Stabilized Coacervate-Based Core-Shell Nanosystems
Co-delivery of different species of protein-encoding polynucleotides, e.g., messenger RNA
(mRNA) and plasmid DNA (pDNA), using the same nanocarrier is an interesting topic that remains
scarcely researched in the field of nucleic acid delivery. The current study hence aims to explore the
possibility of the simultaneous delivery of mRNA (mCherry) and pDNA (pAmCyan) using a single
nanocarrier. The latter is based on gelatin type A, a biocompatible, and biodegradable biopolymer of
broad pharmaceutical application. A core-shell nanostructure is designed with a thermally stabilized
gelatinâpDNA coacervate in its center. Thermal stabilization enhances the coreâs colloidal stability
and pDNA shielding effect against nucleases as confirmed by nanoparticle tracking analysis and gel
electrophoresis, respectively. The stabilized, pDNA-loaded core is coated with the cationic peptide
protamine sulfate to enable additional surface-loading with mRNA. The dual-loaded core-shell
system transfects murine dendritic cell line DC2.4 with both fluorescent reporter mRNA and pDNA
simultaneously, showing a transfection efficiency of 61.4 ± 21.6% for mRNA and 37.6 ± 19.45% for
pDNA, 48 h post-treatment, whereas established commercial, experimental, and clinical transfection
reagents fail. Hence, the unique co-transfectional capacity and the negligible cytotoxicity of the
reported system may hold prospects for vaccination among other downstream applications
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